The contribution of non-homeostatic factors to the recent increase of obesity incidence in Westernized populations such as the U.S., has now come to be appreciated. Ready availability and affordability of palatable, high caloric density foods; activation of responsive CNS pathways that mediate motivation and reward; and loss of effectiveness of endocrine adiposity signals to act at the CNS, may all contribute to excess caloric intake. Our lab has focused on the potential role of the candidate adiposity signals insulin and leptin to modulate 'food reward behavior'. Insulin and leptin act at the medial hypothalamus to regulate energy homeostasis; they also act at CNS sites that mediate reward and motivation. Both decrease performance in behavioral tasks which assess food reward. This occurs at doses that are subthreshold for effects on long-term energy homeostasis, which suggests that the reward-suppressive effects of insulin and leptin are independent of their chronic effects to decrease food intake and regulate body weight. Our recent studies demonstrate that both the medial hypothalamic arcuate nucleus (ARC) and the ventral tegmental area (VTA) are direct sites of action for insulin and leptin to inhibit food reward; and that the effectiveness of insulin and leptin is reversed by high fat diet background. These new insights lead to new questions which will be addressed by pursuing the Specific Aims summarized below. These Aims will evaluate anatomical, behavioral, and developmental aspects of food reward modulation by insulin and leptin. The long-term objective is to delineate the behavioral and synaptic mechanisms that modulate food reward, in relationship to diet or nutritional status. The current Aims will build towards that objective by evaluating: 1) the ability of insulin, leptin, or cell signaling inhibitors to modulate performance in a behavioral task that models diet recidivism, relapse to sucrose-seeking; 2) the effect of high fat diet experience on sucrose self-administration in pre- and post-pubertal rats; and 3) the CNS sites activated in response to sucrose self-administration and modulation of this activation by insulin, leptin, or cell-signaling inhibitors. These studies will elucidate key brain regions and cell signaling pathways which modulate food reward and are targets for insulin and leptin. This could provide the basis for potential therapeutic intervention strategies targeting non-homeostatic, 'reward-based' feeding, a public health problem that is relevant for both adult and pediatric populations in the U.S.